Obesity, which can be defined as a body weight more than 20% above the ideal body weight, is a major health concern in Western societies, since it is accompanied by numerous complications such as hypertension, non-insulin dependent diabetes mellitus and arteriosclerosis, which in turn cause heart disease, stroke and premature death. Obesity is the result of a positive energy balance, as a consequence of increased ratio of caloric intake to energy expenditure. The molecular factors regulating food intake and body weight balance are incompletely understood. B. Staels et al., J. Biol. Chem. 270(27), 15958 (1995); F. Lonnquist et al., Nature Medicine 1(9), 950 (1995)!. Although the genetic and/or environmental factors leading to obesity are poorly understood, several genetic factors have recently been identified.
.beta.-Adrenoceptors have been subclassified as .beta..sub.1 and .beta..sub.2 since 1967. Increased heart rate is the primary consequence of .beta..sub.1 -receptor stimulation, while bronchodilation and smooth muscle relaxation typically result from .beta..sub.2 stimulation. Adipocyte lipolysis was initially thought to be solely a .beta..sub.1 -mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called .beta..sub.3 -adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure
Early developments in this area produced compounds with greater agonist activity for the stimulation of lipolysis (.beta..sub.3 activity) than for stimulation of atrial rate (.beta..sub.1) and tracheal relaxation (.beta..sub.2). These early developments disclosed in Ainsworth et al., U.S. Pat. Nos. 4,478,849 and 4,396,627, were derivatives of phenylethanolamines.
Such selectivity for .beta..sub.3 -adrenoceptors could make compounds of this type potentially useful as antiobesity agents. In addition, these compounds have been reported to show antihyperglycemic effects in animal models of non-insulin-dependent diabetes mellitus.
Recently, assays have been developed which more accurately predict the effects that can be expected in humans. These assays utilize cloned human .beta..sub.3 receptors which have been expressed in Chinese hamster ovary cells. See Emorine et al, Science, 1989, 245:1118-1121; and Liggett, Mol. Pharmacol., 1992, 42:634-637. The agonist and antagonist effects of the various compounds on the cultivated cells provide an indication of the antiobesity and antidiabetic effects of the compounds in humans.
These developments have recently led to the discovery of potent and selective .beta..sub.3 agonists useful for treating obesity and diabetes. For example, U.S. Pat. No. 5,451,677, issued Sep. 19, 1995, hereby incorporated by reference, describes substituted phenyl sulfonamides which are selective .beta..sub.3 agonists useful for treating obesity and diabetes. These phenyl sulfonamide compounds have been found to be useful in the composition and methods of the instant invention.
More recently, a potent and selective .beta..sub.3 agonist, (R)-N-4-2-2-Hydroxy-2-(pyridin-3-yl)ethyl!amino!ethyl!-phenyl!-4-4-(3 -cyclopentylpropyl)-5-tetrazolon- 1-yl!benzenesulfonamide, hereinafter referred to as Compound A, has been identified. ##STR1## The synthesis of Compound A and its utility for treating obesity and diabetes is described in detail in PCT International application publication number WO 95/29159, published Nov. 2, 1995, and in U.S. Pat. No. 5,561,142, issued Oct. 1, 1996. Thus, .beta..sub.3 agonists, such as Compound A, are useful agents for increasing metabolic rate in mammals.
In addition to .beta..sub.3 agonists which act on obesity and diabetes by increasing metabolic rate, researchers have recently cloned the mouse OB gene and its human homologue. Y. Zhang et al., Nature 372, 425 (1994)!. The OB gene product, i.e., the OB protein (also known as leptin), a 167 amino acid polypeptide, has been shown to result in a dose- and time-dependent weight loss when administered to mice via intraperitoneal (IP) injection. M. A. Pelleymounter et al., Science 269, 540 (1995)!. This weight loss effect is attributable to both a reduction in food intake and an increase in energy expenditure. Moreover, since both the mouse and human OB protein have this same effect when administered to mice, the possibility exists that similar effects would also occur in humans. J. L. Halaas et al., Science 269, 543 (1995)!.
Neuropeptide Y (NPY), a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system, is another agent which has been identified as being connected with feeding behavior. Neuropeptide Y is involved in regulating eating behavior and is an extremely potent orixigenic agent See e.g., Stanley, B. G., et al., Peptides 13: 581-587 (1992); Sahu, A. and S. P. Kalra, Trends In Endocrinology And Metabolism 4(7): 217-224 (1993)!. When administered intracerebroventricularly or injected into the hypothalamic paraventricular nucleus (PVN) it elicits eating in satiated rats Clark, J. T., et al., Endocrinology 115(1): 427-429 (1984); Stanley, B. G. and S. F. Leibowitz, Proc. Natl. Acad. Sci. USA 82: 3940-3943 (1985); Stanley, B. G. and S. F. Leibowitz, Life Sci. 35(26): 2635-42 (1984)! and intraventricular injection of antisera to NPY decreases eating Stanley, B. G., et al., Peptides, supra; Sahu, A. and S. P. Kalra, supra!. It has been shown to stimulate appetite in a variety of species and at different stages of development Stanley, B. G., Neuropeptide Y in multiple hypothalamic sites controls eating behavior, endocrine, and autonomic systems for body energy balance, in Neuropeptide Y, W. F. Colmers and C. Wahlestedt, Editor. 1993, Humana Press: Totowa, N.J. p. 457-509.!
NPY elicits a broad range of physiologic effects through activation of at least five receptor subtypes known as Y1 WO 93/09227, published May 13, 1993!, Y2 U.S. Pat. No. 5,545,549, issued Aug. 13, 1996; WO 95/21245, published Aug. 10, 1995!, Y3, Y4 U.S. Pat. No. 5,516,653, issued May 14, 1996; WO 95/17906, published Jul. 6, 1995! and the "atypical Y1," also known as Y5. Although it has recently been reported that the Y5 receptor is the key subtype responsible for the feeding behavior response in mammals WO 96/16542, published Jun. 6, 1996!, it has now been found that the other subtypes (e.g., NPY1, NPY4) may also be involved in weight control, for example by effects on metabolic rate.
The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, for example NPY, galanin, corticotrophin releasing factor (CRF), have been implicated in the mediation of these effects. Additionally, when melanin-concentrating hormone (MCH) was injected into the lateral ventricles of rats, their food consumption increased suggesting that MCH participates in the hypothalamic regulation of feeding behavior; this increase in food consumption was similar to that seen after galanin administration and somewhat less than seen after NPY treatment. D. Qu et al., Nature 380: 243-247 (1996)!. Similarly, intracerebroventricular (ICV) glucagon-like peptide 1 (GLP-1) powerfully inhibited feeding in fasted rats suggesting that central GLP-1 is yet another hypothalamic physiological mediator of satiety. M. D. Turton et al., Nature 379: 69-72 (1996)!.
Other mechanisms and agents which have been implicated as playing a role in the regulation of feeding behavior include serotonin reuptake inhibitors such as dexfenfluramine, urocortin agonists, CCK agonists, 5-HT.sub.2A agonists and 5-HT.sub.2C serotonin receptors. It has been shown that mice lacking 5-HT.sub.2C serotonin receptors are overweight as a result of abnormal control of feeding behavior, thereby establishing a role for this receptor in the serotonergic control of appetite. L. H. Tecott et al., Nature 374: 542-546 (1995)!. A 5-HT.sub.2C agonists would therefore be useful for inhibiting food intake. Indeed, a metabolite of dexfenfluramine, (+)norfenfluramine is an agonist at 5-HT2C receptors M. Spedding et al., Nature 380: 488 (1996)!
It is an object of the present invention to identify compositions useful for the treatment of obesity and/or diabetes. It is a further object of the invention to identify methods of treating obesity or diabetes.
It has now been found that a combination of a metabolic rate modifying agent and an agent which modifies feeding behavior, for example, by reducing total food intake or by reducing caloric intake or selectively reducing intake of specific components of the diet such as carbohydrates or fats, provides effective therapy for treating obesity and diabetes. More specifically, a combination of a .beta..sub.3 agonist and a NPY5 antagonist is particularly preferred for the treatment of obesity and diabetes.